The Cardiac Calcium Handling Machinery is Remodeled in Friedreich's Ataxia.

BACKGROUND

Friedreich's ataxia (FA) is a progressive neurodegenerative disorder caused by an expansion of the GAA triplet repeat in the Frataxin (FXN) gene, leading to reduced frataxin expression. FA commonly affects the heart, causing hypertrophy, heart failure, and fibrosis. The mechanisms of FA-associated cardiac dysfunction may involve disrupted calcium handling and mitochondrial impairment.

OBJECTIVE

To investigate whether abnormalities in calcium handling machinery contributes to cardiac dysfunction in FA.

METHODS

Human left ventricular tissue from FA patients and unaffected donors, and an FXN knock-out (FXN-KO) mouse model, were analyzed. In mice, cardiac function was assessed by echocardiography and ECG. Calcium-handling protein expression was evaluated with Western blotting, RT-qPCR, and immunofluorescence. Single-cell contractility and calcium transients were measured in isolated ventricular myocytes. Mitochondrial function was assessed via confocal imaging to quantify mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS).

RESULTS

FXN-KO mice exhibited significant reductions in ejection fraction, stroke volume, fractional shortening, and cardiac output, with increased LV mass and elevated end-diastolic and end-systolic volumes. Strain analysis revealed increased global and peak longitudinal strain. On ECG, the RR, PR, QRS, and QTc intervals were prolonged. Both human FA and FXN-KO hearts showed downregulation of SERCA2a and Ryr2, with reduced phospholamban phosphorylation. FXN-KO mice also showed upregulation of mitochondrial calcium-handling proteins, including MCU and VDAC, depolarized Δψm, and elevated ROS.

CONCLUSION

Cardiac dysfunction in FA is associated with impaired calcium handling, mitochondrial dysregulation, and systolic impairment, identifying potential molecular targets for therapy.